A Vanadium-Catalyzed Synthesis of Fully Substituted Pyrroles

Article abstract of DOI:10.1021/acs.joc.0c02451

We present a straightforward, fast, inexpensive, and environmentally friendly synthesis of 1,2,3,4,5-pentasubstituted derivatives of pyrrole, which were produced in one-pot reactions of 3-oxoanilides with hydrazides of carboxylic acids, catalyzed by 10 mol % VOSO4·H2O. The reactions were carried out in ethanol in contact with air as the oxidant. The 19 pyrroles obtained were usually crystalline and did not require purification. The reaction tolerates various substituents in both substrates. All products were characterized by infrared, nuclear magnetic resonance, and ultraviolet-visible spectroscopy and elemental analysis. The molecular structures of the products and the intermediates were unambiguously determined by X-ray single-crystal analysis.

Full text of DOI:10.1021/acs.joc.0c02451

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A Vanadium-Catalyzed Synthesis of Fully Substituted Pyrroles
̇
Patrycja Paciorek, Janusz Szklarzewicz,* Bartosz Trzewik, Dariusz Ciez, Wojciech Nitek,
Maciej Hodorowicz, and Anna Jurowska
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ABSTRACT: We present a straightforward, fast, inexpensive, and
environmentally friendly synthesis of 1,2,3,4,5-pentasubstituted
derivatives of pyrrole, which were produced in one-pot reactions of
3-oxoanilides with hydrazides of carboxylic acids, catalyzed by 10
mol % VOSO4·H2O. The reactions were carried out in ethanol in
contact with air as the oxidant. The 19 pyrroles obtained were
usually crystalline and did not require purification. The reaction
tolerates various substituents in both substrates. All products were
characterized by infrared, nuclear magnetic resonance, and ultraviolet−visible spectroscopy and elemental analysis. The molecular
structures of the products and the intermediates were unambiguously determined by X-ray single-crystal analysis.
discovered a simple method of obtaining such compounds, we
optimized the conditions of the reaction (Table 1).
INTRODUCTION
■
Pyrroles make up one of the most important classes of
heterocyclic compounds;1 they exist in nature2 (e.g., in heme,
chlorophyll, and vitamin B12) and have been found to be useful
in materials science,3 medicinal chemistry, drug discovery,4 and
organic synthesis.5
We started our work by examining the reaction in ethanol in
the presence of 1 equiv of [VO(acac)2]. Under these conditions,
pyrrole 1 was isolated in pure crystalline form but with an
unsatisfactorily low yield (entry 1). When we decreased the
amount of [VO(acac)2] to 10 mol %, we observed the formation
of compound C1 at first but on standing (528 h) C1 completely
transformed into 1 with a higher yield (entry 2). Using V2O4 and
V2O5, lower yields were observed (entries 3 and 4, respectively).
Next, the reactions of A1 and B1 in the presence of VOSO4·H2O
in a water/ethanol mixture (entries 5 and 6) and in ethanol
(entries 7−9) were carried out, and the yields of 1 increased to
59% and 69%, respectively. We observed that the yield of 1 was
independent of the amount of VOSO4·H2O in the range of 10−
100 mol %. We thus found that using 10 mol % VOSO4·H2O in
ethanol gave the best yields (entry 7). Finally, we carried out the
synthesis out using isolated imine A1B1 and [VO(acac)2] (entry
10) or VOSO4·H2O (entry 11) as the vanadium complex. These
reactions also gave product 1 with yields comparable to those of
entries 1 and 9, respectively.
Classical methods for the preparation of polysubstituted
pyrroles involve Knorr,6 Paal−Knorr,7 and Hantzsch syntheses.8
The importance of pyrroles has resulted in the continuing
development of new synthetic methods,1 among them a variety
of metal species catalysis strategies,9 to fulfill today’s require-
ments for organic syntheses: simplicity, diversity, readily
available starting materials, possibility of automation, favorable
economic factors, and little environmental influence.10
Although syntheses of functionalized pyrroles from 1,3-
dicarbonyl compounds, catalyzed by transition metals, including
In, Ru, and Ti, have been described in detail in the literature,
they were two-, three-, or four-component reactions.11 In our
studies, we used the vanadium complexes that have proven to be
effective catalysts.12 We have developed the synthesis of the
pyrrole ring in one step from only two substrates (a 3-oxoanilide
and a hydrazide) on the pathway of vanadium-mediated
oxidation followed by a ring closure. In contrast to a previous
report,13 we obtained the products as purely organic
compounds, not metal complexes.
The reaction (see Table 1) was studied in an ethanol/water
mixture or in ethanol. The reaction always proceeds in the
presence of water; as both VOSO4 and ethanol contain water,
water is also liberated during the synthesis of the Schiff base.
Under our conditions, the level of water, present in the system,
was sufficient to ensure dissolution of VOSO4 as a catalyst. As
RESULTS AND DISCUSSION
■
Received: October 21, 2020
Published: January 4, 2021
During the research on vanadium complexes of Schiff bases, we
found that A1B1, obtained in situ from acetoacetanilide A1 (R1
= H, R3 = CH3, and R4 = H) and hydrazide of benzoic acid B1
(R2 = H), spontaneously cyclized under reaction conditions,
giving unexpectedly a crystalline product, which turned out to be
1,2,3,4,5-pentasubstituted pyrrole 1 (Scheme 1). Having
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a
Scheme 1. Synthesis of Pyrroles 1−9 and 11−18 from Anilides A1−A3 and Hydrazides B1−B11
a
We also used 3-phenyl-1,2-oxazole-5-carbohydrazide B10 and H2NHNOC-[CH2]4-CONHNH2 B11 to obtain pyrroles 10 and 19, respectively.
Table 1. Optimizing the Reaction Conditions Using A1 and B1 as Substrates
entry
catalyst (mmol)
solvent
EtOH
EtOH
EtOH
EtOH
EtOH/H2O
EtOH/H2O
EtOH
EtOH
EtOH
time (min)
yield of pyrrole 1 (%)
a
1
2
3
4
5
6
7
8
[VO(acac)2] (1.0)
[VO(acac)2] (0.1)
V2O4 (4.0)
15 + 22
15 + 22
15 + 15
15 + 29
15 + 10
15 + 22
15 + 22
15 + 22
15 + 22
0 + 32
35
46
a
b
a
7
a
V2O5 (8.0)
24
59
59
69
69
69
37
62
a
c
c
VOSO4·H2O (1.0)
VOSO4·H2O (1.0)
VOSO4·H2O (0.1)
VOSO4·H2O (0.5)
VOSO4·H2O (1.0)
[VO(acac)2] (1.0)
VOSO4·H2O (1.0)
a
a
a
a
9
d
10
11
EtOH
EtOH
d
0 + 32
a
b
Reactions were carried out using A1 (2.0 mmol) and B1 (1.0 mmol). Intermediate C1 (R1 = H, R2 = H, and R3 = CH3), identified in Scheme 2,
was formed first. At a 4:1 (v/v) ratio. Reactions were carried out using isolated imine A1B1 (2.0 mmol).
c
d
Table 2. Scope and Limitations of Our Method
3-oxoanilide A
R1 R3
CH3
hydrazide B
type
R2
entry
type
R4
pyrrole
yield (%)
yield (g)
delay before collection (h)
mp (°C)
1
2
3
4
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A2
A2
A2
A2
A2
A3
A3
A3
A1
A4
A5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B1
B3
B4
B5
B6
B1
B4
B9
B11
B1
B1
H
4-NO2
4-F
4-Cl
4-Br
4-CH3
4-OCH3
4-OH
4-NH2
c
1
2
3
4
5
6
7
8
69
30
58
60
66
69
48
60
43
55
52
38
56
70
58
44
45
15
14
0.3122
0.1520
0.2729
0.2922
0.3507
0.3219
0.2316
0.2811
0.2049
0.2858
0.2711
0.2114
0.3163
0.4202
0.3105
0.2485
0.2696
0.0883
0.1155
120
648
288
240
240
216
576
240
456
192
264
408
288
240
240
192
45
280.0−282.0
280.5−282.5
260.0−262.0
265.0−267.0
253.5−255.5
282.0−284.0
241.0−242.5
311.0−313.0
310.0−313.0
247.5−249.5
277.5−279.5
273.0−275.0
295.0−297.0
300.0−302.0
275.0−277.0
295.5−297.0
280.5−282.5
286.5−288.5
317.5−319.5
H
CH3
H
CH3
H
CH3
a
5
H
CH3
6
7
8
9
10
11
H
CH3
H
CH3
H
CH3
H
CH3
9
b
H
CH3
10
11
12
13
14
15
16
17
18
19
−
−
a
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
H
H
H
CH3
CH3
CH3
CH3
H
4-F
a
12
13
4-Cl
4-Br
4-CH3
H
4-Cl
4-NH2
e
a
14
a
15
CH3
16
17
18
n-C5H11
n-C5H11
n-C5H11
Me
432
144
d
19
f
20
21
H
iC3H7
H
H
46
H
Me
−
a
b
c
d
e
With 100 mol % VOSO4·H2O. With 25 mol % VOSO4·H2O. With 3-phenyl-1,2-oxazole-5-carbohydrazide. With 50 mol % [VO(acac)2]. With
f
H2NHNOC-[CH2]4-CONHNH2. Yield of A4B1.
the Schiff base is important for pyrrole formation, the results
presented in Table 1 support the idea that pure ethanol, a
stabilizing Schiff base, increases the reaction yield.
A small drawback of the procedure is the exceedingly long
time required for the complete precipitation of the products;
they were isolated after 120−648 h and after partial evaporation
of the solvent. This time cannot be shortened by either
prolonged refluxing of the reaction mixtures or chilling on
standing. On the contrary, this stage needs no operations before
the filtration of the products.
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Having optimized the reaction conditions, we examined the
scope and limitations of this methodology (Table 2). While 4-F-,
4-Cl-, 4-Br-, 4-Me-, and 4-OH-substituted hydrazides in the
reactions with acetoacetanilide gave the pyrroles in 58−69%
yields (entries 3−6 and 8, respectively), 4-NO2, 4-OMe, 4-NH2,
and 5-phenyl-1,2-oxazol-3-yl groups decreased the yields to 30−
55% (entries 2, 7, 9, and 10, respectively). These results show
that there is no clear connection between the electron-donating
or electron-withdrawing character of the substituents in
hydrazide B and the outcome of the reactions. On the contrary,
introducing a 4-Cl substituent into the phenyl ring of
acetoacetanilide only slightly influenced the yields of the
products (entries 11 and 13−15, respectively) with respect to
unsubstituted acetoacetanilide, with the disappointing exception
of the reaction with 4-fluorobenzoic acid hydrazide (entry 12).
Replacing acetoacetanilide with 3-oxooctanoic acid anilide
gave the corresponding pyrroles in noticeably lower yields of
15−45% (entries 16−18), and 4-methyl-3-oxopentanoic acid
anilide gave no pyrrole product at all (entry 20). In this case,
only the corresponding imine A4B1 was formed. When we used
2-methyl-3-oxo-N-phenylbutanamide [R4 = CH3 (see Scheme
1)] instead of acetoacetanilide, we obtained neither pyrrole nor
imine (entry 21). Finally, aliphatic adipic acid dihydrazide gave
the product in only 14% yield (entry 19). Last but not least, the
size of substituent R3 seems to play a crucial role, as mentioned
in the previous paragraph. The steric hindrance decreases the
yield of the reaction in the following order: Me > n-pentyl > iPr.
A great advantage of the reaction is obtaining pyrroles 1−19
in pure form after simply washing the product with small
portions of ethanol. The results of EA (Table 3) showed
deviations in the range 0.1−0.4% from calculated values. Only in
the case of 6 and C4 did the discrepancy reach 0.5%. In most
cases, the experimental values are lower than the calculated ones,
probably due to small amounts of water remaining in the
products.
Table 3. Experimental and Calculated Compositions of the
Compounds Examined in This Study
Ä
É
Å
Å
Ñ
Ñ
found (%)
calcd (%)
Å
Å
Å
Ñ
Ñ
Ñ
composition
Å
Ñ
Å
Ç
Ñ
Ö
compound
formula
C27H24N4O3
C
H
N
1
71.6
71.7
64.4
64.0
68.8
68.9
66.4
66.6
60.7
61.0
71.6
72.1
69.6
69.7
68.8
69.2
68.1
68.1
69.1
69.4
62.3
62.2
58.5
58.3
57.5
57.4
53.7
54.0
62.4
62.8
5.2
5.3
4.7
4.8
5.1
4.9
4.7
4.8
4.4
4.4
5.7
5.6
5.5
5.4
5.2
5.2
5.4
5.5
4.8
4.8
4.3
4.3
4.4
4.5
3.8
3.9
3.6
3.5
4.5
4.5
12.5
12.4
13.7
13.8
11.6
11.9
11.4
11.5
10.2
10.5
11.8
12.0
11.6
11.6
11.7
12.0
14.6
14.7
13.6
13.5
10.7
10.7
10.0
10.1
10.0
9.9
2
C27H23N5O5·0.5H2O
C27H23FN4O3
3
4
C27H23ClN4O3
5
C27H23BrN4O3
6
C28H26N4O3
7
C28H26N4O4
8
C27H24N4O4
9
C27H25N5O3·0.5H2O
C30H25N5O4
10
11
12
13
14
15
C27H22Cl2N4O3
C27H21Cl2FN4O3·2H2O
C27H21Cl3N4O3·0.5H2O
C27H21BrCl2N4O3
C28H24Cl2N4O3
9.3
9.3
10.4
10.5
The mechanism of the reaction remains unclear. In the first
step, 3-oxoacid anilide A and benzoic acid hydrazide B condense
to give imine AB (see Scheme 1), which is supported by the fact
that the isolated imine A1B1 gave the same product as A1 and
B1, as mentioned above (Table 1, entries 7 and 11). The
addition of the vanadium complex and the aerobic conditions
are vital for the reaction to proceed as in the absence of the
complex or under anaerobic conditions only imine AB could be
isolated.
It is worth noting that in some cases an intermediate
crystalline product C precipitates. It spontaneously transforms
into the appropriate pyrrole on standing. The formation of
intermediate C can be rationalized on the basis of an assumption
that Schiff base AB is oxidized in the presence of the vanadium
complex and air, to give the corresponding 2-oxo derivative,
which condenses with another molecule of hydrazide B to give C
(Scheme 2; also compare Scheme 1). A more detailed
mechanistic proposal that includes the transformations of
intermediate C to the final pyrrole has been suggested on the
basis of the most probable Mannich/annulation pathway
(Scheme 3).
putative byproduct, nitrene R′-NH-N, reacts immediately with
water giving the hydroxylamine derivative.
There have been known examples of complexes of Schiff bases
with vanadium(IV), which bind molecular oxygen14 and are
then promising oxidation catalysts.15 A number of important
biological and industrial processes involve the metal-catalyzed
oxidation of organic substrates, and for this purpose, the use of
O2 as the ultimate oxidant has obvious advantages in terms of
cost and handling use.16
The molecular structures of AB, C, and final pyrroles 1−19
were unequivocally defined by X-ray crystallography, for
example, intermediates A1B4 (R1 = H, R2 = 4-Cl, R3 = CH3,
and R4 = H) and C4 (R1 = H, R2 = 4-Cl, and R3 = CH3) and
pyrrole 4 (R1 = H, R2 = 4-Cl, and R3 = CH3).17 The structures of
these compounds are presented in the Supporting Information.
All new pyrroles were characterized by elemental and spectral
analysis (1H and 13C NMR, IR, and UV−vis in the solid state).
Although the structures of A1B4 and C4 were confirmed by
their crystal structures and their homogeneity, according to the
elemental analysis, the NMR spectra of A1B1, A1B4, C1, and
C4 were complex to such an extent that we were unable to
interpret them.
The first step of pyrrole formation is the Mannich addition of
acetoacetanilide to intermediate C followed by elimination of
hydrazide R′-NH-NH2. The long-term condensation of
hydrazide R′-NH-NH2 with the acetyl fragment of acetoaceta-
nilide leads to the diimine intermediate, hydrazone D, that
undergoes cyclization to the highly substituted pyrrole ring. The
We think that there are two reasons for this complexity: (1)
the existence of the compounds in several (probably at least
three for each) tautomeric forms in solution and (2) the
overlapping of nearly equivalent signals of aromatic rings,
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Scheme 2. Tentative Scheme for the Formation of Intermediates C
compounds is presented in the Experimental Section. Looking at
the complete lists of signals in the NMR spectra of 1−19 (see the
Experimental Section) allows one to notice changes in chemical
Scheme 3. Proposed Scheme of Pyrrole Formation
shifts caused by various substituents, too. For example, the 13
C
NMR spectra of pyrroles 1−19 include signals from C-7 (i.e., in
position 2 of the pyrrole ring by IUPAC rules) in the range of
112.4−113.1 ppm, i.e., within only 0.7 ppm; C-6 atoms
(position 3) absorb at 123.2−123.4 ppm when R1 = H, and
the shifts move to 126.9 ppm when R2 = 4-Cl. C-1−C-5, C-8,
and C-13 (see the Experimental Section for the assignment)
remain nearly entirely insensitive to changes in the substituents.
Generally, the molecules of pyrroles in this study can be divided
into four nearly spectrally independent parts: the pyrrole ring,
-R3, -CONH-C6H4-R1, and -NHCO-C6H4-R2. These remarks
also apply to 1H NMR spectra.
In summary, the reaction apparently proceeds via at least two
intermediates, which, in some cases, can be isolated. In spite of
the fact that the molar ratio of A and B entities in the
intermediates changes from 1:1 in AB to 1:2 in C to 2:1 in the
final pyrroles 1−19, the best yields were obtained for a 2:1
substrate ratio (see Table 1). Bearing in mind that the yields
reached 70% in some cases, it seems that most of the molecules
of A and B finally find their places in the pyrrole system.
especially in the cases of A1B1 and C1. Happily, IR allows one to
trace the changes in the molecular structures on the reaction
path: AB → C → pyrrole (Figure 1).
CONCLUSIONS
■
In summary, we have developed an efficient and environ-
mentally friendly methodology for the direct synthesis of 2,5-
dialkyl-N,N-diaryl-1-[(arylcarbonyl)amino]-1H-pyrrole-3,4-di-
carboxamides from simple and readily available derivatives of
carboxylic acids, catalyzed by VOSO4·H2O. The reactions were
carried out under mild conditions in the presence of air. The
products were obtained usually in crystalline and pure form with
yields of 14−70%. The reaction can be applied to a large number
Contrary to the case for the intermediates, all signals in 1H and
13C spectra of all pyrroles 1−19 could be unequivocally assigned
(with small exceptions in the spectra of 10 and 16−18) without
needing to record DEPT or correlation spectra, on the basis of
only information taken from integration and chemical shifts of
1
signals in the H NMR spectra, aided by the intensities of the
signals in the 13C NMR spectra. The spectral analysis of the
Figure 1. IR spectra of A1B4, C4, and 4 in the ranges of 4000−1700, 1700−1200, and 1200−550 cm−1, respectively.
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and E (cis and trans). As a consequence, the NMR spectra of A1B1 and
A1B4 show the presence of three different species. The poor solubility
of hydrazides, and the substituents in both starting 3-oxoanilides
and hydrazides can be independently changed, which gives the
possibility of obtaining a variety of the title pyrroles.
of A1B1 and A1B4 in C2D6O allowed us to analyze only the 1H and 13
C
signals assigned to the main imine forms and the 1H signals assigned to
the major enamine forms (cis isomers of A1B1 and A1B4). According
to the 1H NMR data, we estimated isomer ratios for A1B1 of
1:0.24:0.05 (imine:cis-enamine:trans-enamine) and for A1B4 of
1:0.20:0.09 (imine:cis-enamine:trans-enamine). Intermediates C1 and
C4 are very slightly soluble in deuterated solvents, so the NMR
measurements were practically impossible.
EXPERIMENTAL SECTION
■
General Methods. We used commercially available substrates
purchased from Aldrich, Alfa Aesar, and Fluorochem without further
purification with the exception of ethyl 3-oxooctanoate and ethyl 4-
methyl-3-oxopentanoate, which were made according to the published
procedure18 and transformed into the corresponding anilides A3 and
A4.19 2-Methyl-3-oxo-N-phenylbutanamide was prepared by methyl-
ation of acetoacetanilide.20
Melting points were measured on an electrothermal IA9000 digital
melting point apparatus and are uncorrected. Diffuse reflectance spectra
were measured in BaSO4 pellets with BaSO4 as a reference using a
Shimadzu UV-3600 apparatus equipped with an ISR-3100 attachment.
Microanalyses of carbon, hydrogen, and nitrogen were performed using
a Vario Micro Cube elemental analyzer. IR spectra were recorded on a
Nicolet iS5 FT-IR (ATR) spectrophotometer with a diamond plate. 1H
NMR and 13C NMR spectra were recorded on a Bruker Avance III 600
or a Bruker Avance II 300 spectrometer. Chemical shifts are given in
parts per million downfield from TMS. Coupling constants are given in
hertz.
Single crystals suitable for X-ray diffraction of compounds A1B4, C4,
and 4 were grown from ethanol. Diffraction data were collected on the
Oxford Diffraction SuperNova four-circle diffractometer at 110 K, using
the Mo (0.71069 Å) Kα radiation source and graphite monochromator.
Cell refinement and data reduction were performed using the
firmware.21 The positions of all non-hydrogen atoms were determined
by direct methods using SIR-97.22 All non-hydrogen atoms were refined
anisotropically using weighted full-matrix least squares on F2.
Refinement and further calculations were carried out using SHELXL-
97.23
2,5-Dimethyl-N-phenyl-1-[(phenylcarbonyl)amino)]-1H-pyrrole-
3,4-dicarboxamide (1). Light yellow, crystalline. Anal. Calcd for
C27H24N4O3: C, 71.7; H, 5.4; N, 12.4. Found: C, 71.6; H, 5.2; N, 12.5.
λmax (BaSO4) (nm): 217, 251, 278. νmax (cm−1): 3338, 3288 (N−H);
3144, 3097, 3061, 3053, 3030 (CAr−H); 2954, 2928 (C−H); 1670,
1653, 1632 [amide I: ν(CO)]; 1621; 1612; 1596 (CArCAr); 1579,
1568, 1556, 1521 [amide II: ν(C−N), δ(N−H)]; 1498, 1487 (CAr
CAr); 1437 δ(C−H); 1421; 1389; 1370; 1339, 1325; 1311, 1277, 1247
[amide III: ν(C−N), δ(N−H)]; 1193; 1177; 1155; 1113, 1102 δ(C−
H)in plane; 1075; 1045; 1024; 1001; 978; 958; 930; 917; 909 δ(pyrrole
ring); 899; 893; 853, 845 ν(N−N); 832; 808; 796; 789; 751, 699, 689
1
[amide IV: δ(OCN)]; 662; 625; 618; 593; 571. H NMR (C2D6OS,
Ethyl 4-Methyl-3-oxopentanoate. Yield: 48%. Colorless liquid. Bp:
300 MHz): δ 11.71 (s, 1H, H-7), 10.73 (s, 2H, H-8), 8.03 (dd, 2H, J =
8.3, 1.3, H-4), 7.71 (tt, 1H, J = 6.8, 1.3, H-6), 7.69 (dd, 4H, J = 8.5, 1.1,
H-1), 7.61 (ddt, 2H, J = 8.1, 6.6, 1.5, H-5), 7.34 (ddt, 4H, J = 8.5, 7.4,
1.8, H-2), 7.08 (tt, 2H, J = 7.4, 1.0, H-3), 2.35 (s, 6H, H-9). 13C{1H}
NMR (C2D6OS, 75 MHz): δ 165.9, 164.2, 139.0, 132.8, 132.7, 131.2,
128.7, 128.7, 127.6, 123.3, 119.6, 112.7, 10.4.
92−97 °C/17 Torr (lit.,24 90−91 °C/16 Torr).
Ethyl 3-Oxooctanoate. Yield: 57%. Colorless liquid. Bp: 123−128
°C/17 Torr (lit.,25 124−125 °C/17 Torr).
3-Oxo-N-phenyloctanamide (A3). Yield: 40%. White needles (from
petroleum ether, bp 60−90 °C). Mp: 82.5−84.0 °C (lit.,26 83−84 °C).
4-Methyl-3-oxo-N-phenylpentanamide (A4). Yield: 58%. Light
rose oil.
1-[(4-Nitrobenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-pyr-
role-3,4-dicarboxamide (2). Light yellow, crystalline. Anal. Calcd for
C27H24N5O5.5: C, 64.0; H, 4.8; N, 13.8. Found: C, 64.4; H, 4.7; N, 13.7.
λmax (BaSO4) (nm): 204, 260, 279, 366. νmax (cm−1): 3235, 3208 (N−
H); 3148, 3114, 3099, 3076, 3053, 3040 (CAr−H); 2994, 2951, 2920
(C−H); 1697, 1664 [amide I: ν(CO)]; 1626; 1608; 1596 (CAr
CAr); 1566, 1559 1517 [amide II: ν(C−N), δ(N−H)]; 1496, 1482
(CArCAr); 1443 δ(C−H); 1406; 1375; 1351; 1328; 1315; 1303,
1273, 1254 [amide III: ν(C−N), δ(N−H)]; 1202; 1187; 1173; 1155;
1113, 1099, 1073 δ(C−H)in plane; 1028; 1013; 971; 941; 926; 912; 895;
864, 856 [ν(N−N)]; 843; 795; 782; 749, 741, 726, 711, 689 [amide IV:
δ(OCN)]; 668; 628; 620; 611. 1H NMR (C2D6OS, 300 MHz): δ 12.06
(s, 1H, H-7), 10.70 (s, 2H, H-8), 8.44 (dt, 2H, J = 8.9, 2.2, H-5), 8.25
(dt, 2H, J = 8.9, 2.2, H-4), 7.67 (dd, 4H, J = 8.4, 0.8, H-1), 7.34 (ddt, 4H,
J = 8.4, 7.5, 1.9, H-2), 7.08 (tt, 2H, J = 7.4, 1.1, H-3), 2.35 (s, 6H, H-9).
13C{1H} NMR (C2D6OS, 75 MHz): δ 164.6, 164.1, 149.8, 138.9, 136.7,
General Procedure for the Synthesis of Pyrroles 1−19. 3-
Oxoanilide A (2.0 mmol) and hydrazide B (1.0 mmol) in ethanol (30
mL) were refluxed (15 min) on the heating mantle. Then, VOSO4·H2O
(0.1, 0.25, or 1 mmol) or [VO(acac)2] (0.5 mmol) (see Table 2) was
added, and reflux was continued for 22 min. During the course of the
reaction, the color of the mixture changed, after addition of the
vanadium(IV) complex, to deep yellow and then to green, which
indicated the optimal time of reflux. Next, the excess of the vanadium
complex was filtered off and the reaction mixture was left to crystallize at
room temperature. Upon standing at room temperature, the solution
became dark brown or red and then, after all of the product had
precipitated (beware that in some cases long light fibers of intermediate
C were first formed), light yellow or brown.
After slow evaporation for 120−648 h (to ∼1/3 of the starting volume
of the mixture), the precipitation of the product was completed, and the
product was filtered off, washed several times with ethanol, and dried at
room temperature. In some cases, the pyrroles crystallized with one or
half of one molecule of water per molecule of the product.
Other methods of synthesis like microwave/ultrasonic waves were
also used, but the problem was that the method described for the first
time herein is the least expensive, as it does not require extra energy
during reaction (standing). The yield of the reaction was also not
higher. The formation of larger crystals of pyrrole, upon slow solvent
evaporation, increases also the purity of the products.
132.6, 129.3, 128.7, 123.9, 123.4, 119.6, 112.9, 10.3.
1-[(4-Fluorobenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-pyr-
role-3,4-dicarboxamide (3). Light yellow, crystalline. Anal. Calcd for
C27H23FN4O3: C, 68.9; H, 4.9; N, 11.9. Found: C, 68.8; H, 5.1; N, 11.6.
λmax (BaSO4) (nm) 251, 281, 313; νmax (cm−1) 3341, 3293 (N−H);
3212; 3139, 3099, 3070, 3051, 3023 (CAr−H); 2955, 2926 (C−H);
1667, 1659, 1634 [amide I: ν(CO)]; 1618; 1611; 1597 (CArCAr);
1569, 1557, 1521 [amide II: ν(C−N), δ(N−H)]; 1499, 1486 (CAr
CAr); 1438 [δ(C−H)]; 1423; 1391; 1371; 1342; 1309, 1279, 1242
[amide III: ν(C−N), δ(N−H)]; 1193; 1175; 1162; 1144; 1111, 1099
[δ(C−H)in plane]; 1076; 1045; 1034; 1027; 1014; 1001; 977; 964; 960;
918; 910; 899; 853 [ν(N−N)]; 817; 795; 785; 752, 694 [amide IV:
δ(OCN)]; 668; 624; 580; 1H NMR (C2D6OS, 300 MHz) δ 11.73 (s,
1H, H-7), 10.70 (s, 2H, H-8), 8.09 [ddt, 2H, J = 8.9, 5.4 (H-4-F), 2.6,
The spectroscopic data for 1−19, A3, A1B1, A1B4, C1, and C4
(pyrroles and selected substrates and intermediates) are given below.
The main imine forms of A1B1 and A1B4 exist in C2D6O solutions in
equilibrium with two tautomeric enamine forms: geometric isomers Z
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Article
H-4], 7.68 (dd, 4H, J = 8.5, 1.0, H-1), 7.46 [ddt, 2H, J = 8.9, 8.9 (H-5-
F), 2.6, H-5], 7.34 (ddt, 4H, J = 8.5, 7.4, 1.7, H-2), 7.07 (tt, 2H, J = 7.4,
1.0, H-3), 2.33 (s, 6H, H-9); 13C{1H} NMR (C2D6OS, 75 MHz) δ
164.9, 164.1, 139.0, 132.8, 130.5 (d, J = 9.0), 128.7, 127.6 (d, J = 2.5),
119.6, 123.4, 115.8 (d, J = 22.0), 112.8, 10.4.
(C2D6OS, 300 MHz): δ 11.54 (s, 1H, H-7), 10.72 (s, 2H, H-8), 8.00
(dt, 2H, J = 8.9, 2.4, H-4), 7.69 (dd, 4H, J = 8.5, 1.0, H-1), 7.34 (ddt, 4H,
J = 8.5, 7.4, 1.9, H-2), 7.14 (tt, 2H, J = 8.9, 2.4, H-5), 7.08 (tt, 2H, J = 7.4,
1.1, H-3), 3.87 (s, 3H, OCH3), 2.33 (s, 6H, H-9). 13C{1H} NMR
(C2D6OS, 75 MHz): δ 165.3, 164.2, 162.7, 139.0, 133.0, 129.7, 128.7,
123.3, 123.2, 119.6, 114.0, 112.6, 55.5, 10.4.
1-[(4-Chlorobenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-pyr-
role-3,4-dicarboxamide (4). Light yellow, crystalline. Anal. Calcd for
C27H23ClN4O3: C, 66.6; H, 4.8; N, 11.5. Found: C, 66.4; H, 4.7; N,
11.4. λmax (BaSO4) (nm): 213, 249, 279. νmax (cm−1): 3333, 3295 (N−
H); 3214; 3139, 3096, 3073, 3051, 3024 (CAr−H); 2929, 2916, 2813
(C−H); 1668, 1658, 1635 [amide I: ν(CO)]; 1618; 1612; 1596
(CArCAr); 1569, 1557, 1524 [amide II: ν(C−N), δ(N−H)]; 1498,
1488 (CArCAr); 1439 δ(C−H); 1403; 1387; 1342; 1306, 1295, 1279
[amide III: ν(C−N), δ(N−H)]; 1247; 1237; 1193; 1181; 1156; 1108,
1097 δ(C−H)in plane; 1074; 1047; 1032; 1016; 983; 976; 967; 959; 919;
911; 900; 848, 833 ν(N−N); 798; 791; 756, 751, 724, 697, 686 [amide
IV: δ(OCN)]; 667; 627; 617; 606; 593; 572. 1H NMR (C2D6OS, 300
MHz): δ 11.79 (s, 1H, H-7), 10.71 (s, 2H, H-8), 8.04 (dt, 2H, J = 8.7,
2.2, H-4), 7.70 (dd, 2H, J = 8.7, 2.3, H-5), 7.68 (dd, 4H, J = 8.6, 1.0, H-
1), 7.34 (ddt, 4H, J = 8.5, 7.4, 1.8, H-2), 7.07 (tt, 2H, J = 7.4, 1.0, H-3),
2.33 (s, 6H, H-9). 13C{1H} NMR (C2D6OS, 75 MHz): δ 165.0, 164.1,
139.0, 137.6, 132.7, 129.9, 129.6, 128.9, 128.7, 123.4, 119.6, 112.8, 10.4.
1-[(4-Bromobenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-pyr-
role-3,4-dicarboxamide (5). Light yellow, crystalline. Anal. Calcd for
C27H23BrN4O3: C, 61.0; H, 4.4; N, 10.5. Found: C, 60.7; H, 4.4; N,
10.2. λmax (BaSO4) (nm): 210, 256, 278. νmax (cm−1): 3333, 3296 (N−
H); 3214; 3139, 3099, 3071, 3052, 3027 (CAr−H); 2930, 2917, 2808
(C−H); 1668, 1657, 1635 [amide I: ν(CO)]; 1617; 1611; 1595
(CArCAr); 1568, 1556, 1524 [amide II: ν(C−N), δ(N−H)]; 1497,
1487 (CArCAr); 1439 δ(C−H); 1419; 1387; 1370; 1341; 1310, 1302,
1290, 1278 [amide III: ν(C−N), δ(N−H)]; 1246; 1234; 1193; 1181;
1156; 1114, 1107 δ(C−H)in plane; 1074; 1048; 1032; 1014; 984; 957;
927; 919; 911; 899; 853; 844, 833 ν(N−N); 797; 791; 755, 749, 719,
696, 685 [amide IV: δ(OCN)]; 667; 626; 616; 592. 1H NMR
(C2D6OS, 300 MHz): δ 11.79 (s, 1H, H-7), 10.70 (s, 2H, H-8), 7.95
(dt, 2H, J = 8.6, 2.1, H-4), 7.84 (dt, 2H, J = 8.6, 2.1, H-5), 7.67 (dd, 4H, J
= 8.6, 1.1, H-1), 7.34 (ddt, 4H, J = 8.6, 7.4, 1.8, H-2), 7.07 (tt, 2H, J =
7.4, 0.9, H-3), 2.33 (s, 6H, H-9). 13C{1H} NMR (C2D6OS, 75 MHz): δ
165.1, 164.1, 139.0, 132.7, 131.8, 130.3, 129.7, 128.7, 126.5, 123.4,
119.6, 112.8, 10.4.
1-[(4-Hydroxybenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-
pyrrole-3,4-dicarboxamide (8). Cream, crystalline. Anal. Calcd for
C27H24N4O4: C, 69.2; H, 5.2; N, 12.0. Found: C, 68.8; H, 5.2; N, 11.7.
λmax (BaSO4) (nm): 204, 260, 279. νmax (cm−1): 3337 (O−H); 3305,
3229 (N−H); 3175, 3152, 3055, 3028, 3016 (CAr−H); 2969, 2932,
2918 (C−H); 1662, 1637, 1628 [amide I: ν(CO); 1622; 1609; 1598
(CArCAr); 1586, 1568, 1553, 1526 [amide II: ν(C−N), δ(N−H);
1509; 1500, 1489 (CArCAr); 1442 δ(C−H); 1422; 1390; 1371; 1338;
1314; 1298, 1280, 1252 [amide III: ν(C−N), δ(N−H)]; 1236; 1218;
1195; 1176; 1155; 1117, 1100 δ(C−H)in plane; 1076; 1046; 1024; 1001;
982; 963; 930; 921; 915; 901; 850 ν(N−N); 820; 794; 785; 772; 754,
1
716, 695, 688 [amide IV: δ(OCN)]; 660; 624; 613; 583. H NMR
(C2D6OS, 300 MHz): δ 11.42 (s, 1H, H-7), 10.72 (s, 2H, H-8), 10.31
(s, 1H, H-14), 7.90 (dt, 2H, J = 8.8, 2.4, H-4), 7.68 (dd, 4H, J = 8.6, 1.0,
H-1), 7.34 (ddt, 4H, J = 8.4, 7.5, 1.8, H-2), 7.07 (tt, 2H, J = 7.4, 1.1, H-
3), 6.94 (dt, 2H, J = 8.8, 2.4, H-5), 2.32 (s, 6H, H-9). 13C{1H} NMR
(C2D6OS, 75 MHz): δ 165.4, 164.2, 161.4, 139.0, 133.0, 129.8, 128.7,
123.4, 121.6, 119.6, 115.8, 112.6, 10.4.
1-[(4-Aminobenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-pyr-
role-3,4-dicarboxamide (9). Light yellow, crystalline. Anal. Calcd for
C27H26N5O3.5: C, 68.1; H, 5.5; N, 14.7. Found: C, 68.1; H, 5.4; N, 14.6.
λmax (BaSO4) (nm): 205, 213, 279, 293. νmax (cm−1): 3474, 3354
ν(NH2); 3304, 3222 ν(N−H); 3149, 3060, 3048, 3022 ν(CAr−H);
2968, 2929 ν(C−H); 1658, 1642, 1629 [amide I: ν(CO)]; 1602
ν(CArCAr); 1568, 1555, 1526 [amide II: ν(C−N), δ(N−H)]; 1510;
1498, 1490 ν(CArCAr); 1440 δ(C−H); 1422; 1391; 1370; 1340;
1313; 1286, 1279, 1251 [amide III: ν(C−N), δ(N−H)]; 1236; 1195;
1185; 1176; 1157; 1135; 1116, 1107 δ(C−H)in plane; 1075; 1047; 1030;
1000; 982; 973; 962; 949; 929; 919; 913; 899; 854, 841 ν(N−N); 828;
795; 788; 771, 762, 755, 751, 712, 697, 686 [amide IV: δ(OCN)]; 668;
660; 628; 620; 582. 1H NMR (C2D6OS, 300 MHz): δ 11.16 (s, 1H, H-
7), 10.72 (s, 2H, H-8), 7.74 (d, 2H, J = 8.7, H-4), 7.68 (dd, 4H, J = 8.5,
1.0, H-1), 7.33 (ddt, 4H, J = 8.5, 7.4, 1.8, H-2), 7.07 (tt, 2H, J = 7.4, 1.1,
H-3), 6.65 (d, 2H, J = 8.7, H-5), 5.93 (s, 2H, NH2), 2.30 (s, 6H, H-9).
13C{1H} NMR (C2D6OS, 75 MHz): δ 165.6, 164.3, 153.0, 139.0, 133.3,
1-[(4-Methylbenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-
pyrrole-3,4-dicarboxamide (6). Light yellow, crystalline. Anal. Calcd
for C28H26N4O3: C, 72.1; H, 5.6; N, 12.0. Found: C, 71.6; H, 5.7; N,
11.8. λmax (BaSO4) (nm): 204, 279, 257. νmax (cm−1): 3322, 3291 (N−
H); 3226; 3143, 3109, 3094, 3075, 3053, 3040, 3028 (CAr−H); 2956,
2923 (C−H); 1666, 1651, 1637 [amide I: ν(CO)]; 1618; 1612;
1597 (CArCAr); 1568, 1556, 1525 [amide II: ν(C−N), δ(N−H)];
1498, 1485 (CArCAr); 1440 δ(C−H); 1422; 1389; 1370; 1340; 1310;
1302, 1286, 1279, 1248 [amide III: ν(C−N), δ(N−H)]; 1216; 1194;
1186; 1177; 1157; 1114, 1108, 1101 δ(C−H)in plane; 1074; 1046; 1038;
1031; 1020; 999; 979; 956; 928; 919, 909; 898; 855, 836 ν(N−N); 793;
781; 749, 712, 699, 685 [amide IV: δ(OCN)]; 669; 624; 581. 1H NMR
(C2D6OS, 300 MHz): δ 11.62 (s, 1H, H-8), 10.71 (s, 2H, H-7), 7.92
(dd, 2H, J = 8.6, 0.7, H-4), 7.68 (dd, 4H, J = 8.6, 1.0, H-1), 7.41 (dd, 2H,
J = 8.6, 0.7, H-5), 7.34 (ddt, 4H, J = 8.6, 7.4, 1.8, H-2), 7.07 (tt, 2H, J =
7.4, 1.2, H-3), 2.42 (s, 3H, CH3), 2.33 (s, 6H, H-9). 13C{1H} NMR
(C2D6OS, 75 MHz): δ 165.8, 164.2, 142.9, 139.0, 132.9, 129.2, 128.7,
128.3, 127.7, 123.4, 119.6, 112.7, 21.0, 10.4.
1-[(4-Methoxybenzoyl)amino]-N,N′-diphenyl-2,5-dimethyl-1H-
pyrrole-3,4-dicarboxamide (7). Light yellow, crystalline. Anal. Calcd
for C28H26N4O4: C, 69.7; H, 5.4; N, 11.6. Found: C, 69.6; H, 5.5; N,
11.6. λmax (BaSO4) (nm): 204, 215, 259, 283, 320. νmax (cm−1): 3324,
3291 (N−H); 3224; 3140, 3095, 3068, 3054, 3040, 3021 (CAr−H);
2964, 2930, 2917, 2841 (C−H); 1668, 1652, 1635 [amide I: ν(C
O)]; 1608; 1597 (CArCAr); 1567, 1555, 1528 [amide II: ν(C−N),
δ(N−H)]; 1510; 1498, 1459 (CArCAr); 1440 δ(C−H); 1420; 1388;
1369; 1335; 1323; 1313; 1292, 1265, 1249 [amide III: ν(C−N), δ(N−
H)]; 1193; 1176; 1157; 1124; 1110, 1102 δ(C−H)in plane; 1074; 1034;
980; 971; 961; 949; 927; 913; 899; 852, 842 ν(N−N); 795; 779; 754,
748, 711, 699, 694, 686 [amide IV: δ(OCN)]; 637; 623; 581. 1H NMR
129.4, 128.7, 123.3, 119.6, 117.1, 112.6, 112.4, 10.5.
1-[(5-Phenylisoxazol-3-yl)amino]-2,5-dimethyl-N-phenyl-1H-
pyrrole-3,4-dicarboxamide (10). Light yellow, crystalline. Anal. Calcd
for C30H25N5O4: C, 69.4; H, 4.8; N, 13.5. Found: C, 69.1; H, 4.8; N,
13.6. λmax (BaSO4) (nm): 205, 214, 260, 280, 354. νmax (cm−1): 3466
(O−H); 3301, 3262 ν(N−H); 3214; 3180, 3129, 3076, 3058, 3037
(CAr−H); 2975, 2947, 2922 ν(C−H); 1726, 1646 [amide I: ν(C
O)]; 1619; 1610; 1595 ν(CArCAr); 1565, 1550 [amide II: ν(C−N),
δ(N−H)]; 1498, 1486 ν(CArCAr); 1444 δ(C−H); 1421; 1399; 1386;
1372; 1338; 1316; 1280; 1258, 1234 [amide III: ν(C−N), δ(N−H)];
1204; 1192; 1178; 1156; 1123, 1105 δ(C−H)in plane; 1095; 1077; 1070;
1049; 1041; 1033; 1025; 1003; 997; 977; 963; 947; 928; 916; 907; 901;
885; 855, 843 ν(N−N); 822; 796; 785; 765, 752, 689 [amide IV:
δ(OCN)]; 676; 633; 616; 572. 1H NMR (C2D6OS, 300 MHz): δ 12.37
(s, 1H, H-7), 10.71 (s, 2H, H-8), 7.69 (dd, 4H, J = 8.5, 0.9, H-1), 7.62
(s, 1H, H-14), 7.99−8.01 (2H, m), 7.56−7.61 (3H, m, H-17, H-18, H-
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19), 7.34 (ddt, 4H, J = 8.5, 7.5, 1.9, H-2), 7.08 (tt, 2H, J = 7.6, 1.1, H-3),
2.35 (s, 6H, H-9). 13C{1H} NMR (C2D6OS, 75 MHz): δ 171.1, 164.0,
158.2, 157.3, 138.9, 132.4, 131.1, 129.3, 128.7, 125.9, 125.9, 123.4,
119.6, 113.0, 100.3, 100.3, 10.3, 10.3.
8.8, H-4), 7.83 (d, 2H, J = 8.4, H-5), 7.70 (d, 4H, J = 8.8, H-1), 7.38 (d,
4H, J = 8.8, H-2), 2.31 (s, 6H, H-9). 13C{1H} NMR (C2D6OS, 150
MHz): δ 165.1, 164.0, 137.9, 132.8, 131.8, 130.2, 129.7, 128.5, 126.9,
126.5, 121.1, 112.7, 10.3.
1-[(4-Methylbenzoyl)amino]-N,N′-bis(4-chlorophenyl)-2,5-di-
methyl-N-phenyl-1H-pyrrole-3,4-dicarboxamide (15). Light brown,
crystalline. Anal. Calcd for C28H24Cl2N4O3: C, 62.8; H, 4.5; N, 10.5.
Found: C, 62.4; H, 4.5; N, 10.4. λmax (BaSO4) (nm): 220, 280, 311. νmax
(cm−1): 3322, 3220 (N−H); 3125, 3083 (CAr−H); 2951, 2922 (C−
H); 1671, 1651, 1639 [amide I: ν(CO)]; 1612; 1592 (CArCAr);
1568, 1553, 1515 [amide II: ν(C−N), δ(N−H)]; 1491 (CArCAr);
1420; 1402; 1387; 1370; 1340; 1302, 1282, 1245, 1240 [amide III:
ν(C−N), δ(N−H)]; 1194; 1181; 1094 δ(C−H)in plane; 1039; 1015;
965; 947; 926; 917; 904; 860; 849, 835, 818 ν(N−N); 798; 780; 764,
1-[(Phenyl)amino]-N,N′-bis(4-chlorophenyl)-2,5-dimethyl-1H-
pyrrole-3,4-dicarboxamide (11). Light brown, crystalline. Anal. Calcd
for C27H22Cl2N4O3: C, 62.2; H, 4.3; N, 10.7. Found: C, 62.3; H, 4.3; N,
10.7. λmax (BaSO4) (nm): 214, 283, 303. νmax (cm−1): 3247, 3212 (N−
H); 3190, 3110, 3065, 3053, 3032 (CAr−H); 2993, 2927 (C−H); 1697,
1632 [amide I: ν(CO)]; 1602; 1589 (CArCAr); 1545, 1535,
[amide II: ν(C−N), δ(N−H)]; 1515; 1489 (CArCAr); 1449 δ(C−
H); 1424; 1409; 1402; 1391; 1379; 1330; 1306; 1291, 1272, 1249,
1243 [amide III: ν(C−N), δ(N−H)]; 1196, 1176; 1099, 1091, 1074
δ(C−H)in plane; 1054; 1025; 1013; 992; 973; 956; 939; 931; 916; 898;
862, 849 ν(N−N); 823; 810; 786; 767; 749, 717; 690 [amide IV:
δ(OCN)]; 647; 630; 596. 1H NMR (C2D6OS, 300 MHz): δ 11.72 (s,
1H, H-7), 10.75 (s, 2H, H-8), 8.02 (ddt, 2H, J = 8.3, 1.8, 1.3, H-4), 7.71
(d, 4H, J = 8.9, H-1), 7.67 (t, 1H, J = 1.4, H-6), 7.60 (ddt, 2H, J = 8.1,
6.6, 1.4, H-5), 7.39 (d, 4H, J = 8.9, H-2), 2.33 (s, 6H, H-9). 13C{1H}
NMR (C2D6OS, 75 MHz): δ 165.9, 164.1, 137.9, 133.0, 132.7, 131.2,
128.8, 128.6, 127.6, 126.9, 121.1, 112.7, 10.4.
1
745; 710, 680 [amide IV: δ(OCN)]; 647; 636; 614; 581. H NMR
(C2D6OS, 600 MHz): δ 11.63 (s, 1H, H-7), 10.75 (s, 2H, H-8), 7.92
(dd, 2H, J = 8.2, 1.6, H-4), 7.71 (dt, 4H, J = 8.9, 2.5, H-1), 7.41 (dd, 2H,
J = 8.5, 0.6, H-5), 7.38 (dt, 4H, J = 8.9, 2.5, H-2), 2.41 (s, 3H, H-14),
2.32 (s, 6H, H-9). 13C{1H} NMR (C2D6OS, 150 MHz): δ 165.8, 164.1,
142.9, 137.9, 133.0, 129.2, 128.5, 128.3, 127.7, 126.9, 121.1, 112.6, 21.0,
10.4.
1-[(4-Fluorobenzoyl)amino]-N,N′-bis(4-chlorophenyl)-2,5-di-
methyl-N-phenyl-1H-pyrrole-3,4-dicarboxamide Monohydrate
(12). Light brown, crystalline. Anal. Calcd for C27H25Cl2FN4O5: C,
58.3; H, 4.5; N, 10.1. Found: C, 58.5; H, 4.4; N, 10.0. λmax (BaSO4)
(nm): 211, 278, 321. νmax (cm−1): 3421 (O−H); 3339, 3306 (N−H);
3186; 3113, 3062, 3007 (CAr−H); 2973, 2927 (C−H); 1679, 1635
[amide I: ν(CO)]; 1602; 1597 (CArCAr); 1574, 1550, 1520
[amide II: ν(C−N), δ(N−H)]; 1490 (CArCAr); 1456; 1447 δ(C−
H), 1424; 1401; 1385; 1338; 1320; 1305, 1281; 1238, 1232 [amide III:
ν(C−N), δ(N−H)]; 1193; 1174; 1158; 1095, 1091 δ(C−H)in plane
;
1047; 1011; 967; 952; 946; 930; 922; 898; 878; 864; 848; 836, 829
ν(N−N); 821; 795; 784; 769, 750, 710, 677 [amide IV: δ(OCN)]; 644;
625; 609; 600; 581. 1H NMR (C2D6OS, 600 MHz): δ 11.74 (s, 1H, H-
7), 10.73 (s, 2H, H-8), 8.09 [ddt, 2H, J = 8.9, 5.4 (H-4-F), 2.5, H-4],
7.70 (dt, 4H, J = 8.9, 2.5, H-1), 7.45 [ddt, 2H, J = 8.9, 8.9 (H-5-F), 2.5,
H-5], 7.38 (dt, 4H, J = 8.9, 2.6, H-2), 2.32 (s, 6H, H-9). 13C{1H} NMR
(C2D6OS, 150 MHz): δ 164.9, 164.3 (d, J = 160.3), 164.0, 137.9, 132.9,
130.5 (d, J = 9.3), 128.5, 127.6 (d, J = 2.1), 126.9, 121.1, 115.8 (d, J =
21.9), 112.7, 10.3.
1-[(4-Chlorobenzoyl)amino]-N,N′-bis(4-chlorophenyl)-2,5-di-
methyl-N-phenyl-1H-pyrrole-3,4-dicarboxamide Hemihydrate (13).
Light brown, crystalline. Anal. Calcd for C27H22Cl3N4O3.5: C, 57.4; H,
3.9; N, 9.9. Found: C, 57.5; H, 3.8; N, 10.0. λmax (BaSO4) (nm): 216,
259, 282. νmax (cm−1): 3257 (N−H); 3192; 3123, 3094 (CAr−H);
2971, 2920 (C−H); 1667, 1662 [amide I: ν(CO)]; 1608; 1593
(CArCAr); 1563, 1551 [amide II: ν(C−N), δ(N−H)]; 1506; 1491,
1482 (CArCAr); 1456; 1439 δ(C−H); 1408; 1398; 1383; 1378; 1363;
1325; 1299; 1293, 1273, 1251, 1243 [amide III: ν(C−N), δ(N−H)];
1200; 1188; 1182; 1171; 1116 1095 δ(C−H)in plane; 1044; 1012; 970;
951; 944; 931; 922; 906; 864; 848, 826 ν(N−N); 821; 804; 797; 786;
770; 764, 753, 728, 700 [amide IV: δ(OCN)]; 668; 627, 612. 1H NMR
(C2D6OS, 300 MHz): δ 11.80 (s, 1H, H-7), 10.72 (s, 2H, H-8), 8.02
(dt, 2H, J = 8.7, 2.2, H-4), 7.70 (dt, 2H, J = 8.7, 2.2, H-5), 7.70 (dt, 4H, J
= 8.9, 2.7, H-1), 7.38 (dt, 4H, J = 8.9, 2.7, H-2), 2.31 (s, 6H, H-9).
13C{1H} NMR (C2D6OS, 75 MHz): δ 165.0, 164.0, 137.9, 137.6, 132.8,
1-[(Phenyl)amino]-N,N′-diphenyl-2,5-dipentyl-1H-pyrrole-3,4-di-
carboxamide (16). Light brown, crystalline. Anal. Calcd for
C35H40N4O3: C, 74.4; H, 7.1; N, 9.9. Found: C, 74.3; H, 7.1; N, 9.9.
λmax (BaSO4) (nm): 209, 280. νmax (cm−1): 3260, 3238 ν(N−H); 3133,
3060, 3040 ν(CAr−H); 2959, 2930, 2872, 2855 ν(C−H); 1667, 1633
[amide I: ν(CO)]; 1598 ν(CArCAr); 1562, 1538 [amide II: ν(C−
N), δ(N−H)]; 1499, 1488 ν(CArCAr); 1466; 1439 δ(C−H); 1380;
1323, 1304, 1288, 1254 [amide III: ν(C−N), δ(N−H)]; 1216; 1206;
1178; 1156; 1117, 1103 δ(C−H)in plane; 1073; 1028; 1001; 969; 937;
915; 897; 870; 841 ν(N−N); 801; 772; 749, 690 [amide IV: δ(OCN)];
631; 614; 579. 1H NMR (C2D6OS, 300 MHz): δ 11.66 (s, 1H, H-7),
10.53 (s, 2H, H-8), 7.96 (ddt, 2H, J = 8.2, 1.6, 1.3, H-4), 7.70 (tt, 1H, J =
7.4, 1.8, H-6), 7.65 (dd, 4H, J = 7.5, 1.2, H-1), 7.61 (tt, 2H, J = 7.0, 1.5,
H-5), 7.32 (ddt, 4H, J = 8.4, 7.5, 1.8, H-2), 7.06 (tt, 2H, J = 7.4, 0.9, H-
3), 2.80 (ddd, 2H, J = 14.6, 9.4, 6.2, H-9′), 2.62 (ddd, 2H, J = 14.6, 9.4,
6.2, H-9), 1.38−1.63 (m, 4H, H-10), 1.11−1.33 (m, 8H, H-11, H-12),
0.75 (t, 6H, H-13). 13C{1H} NMR (C2D6OS, 75 MHz): δ 166.2, 164.2,
139.0, 136.3, 132.5, 131.5, 128.8, 128.6, 127.4, 123.3, 119.5, 113.0, 30.9,
28.2, 24.0, 21.4, 13.5.
1-[(4-Chlorobenzoyl)amino]-N,N′-diphenyl-2,5-dipentyl-1H-pyr-
role-3,4-dicarboxamide (17). Light brown, crystalline. Anal. Calcd for
C35H39ClN4O3: C, 70.2; H, 6.6; N, 9.4. Found: C, 70.2; H, 6.6; N, 9.2.
λmax (BaSO4) (nm): 205, 246, 278. νmax (cm−1): 3260, 3243 ν(N−H);
3133, 3056, 3039 ν(CAr−H); 2955, 2928, 2870, 2853 ν(C−H); 1666,
1634 [amide I: ν(CO)]; 1597 ν(CArCAr); 1562, 1540 [amide II:
ν(C−N), δ(N−H)]; 1499, 1486 ν(CArCAr); 1466; 1439 δ(C−H);
1380; 1324, 1300, 1277, 1254 [amide III: ν(C−N), δ(N−H)]; 1215;
1206; 1178; 1155; 1112, 1096 δ(C−H)in plane; 1074; 1029; 1016; 984;
966; 935; 915; 898; 844 ν(N−N); 800; 749, 690 [amide IV: δ(OCN)];
666; 621; 614; 579. 1H NMR (C2D6OS, 300 MHz): δ 11.75 (s, 1H, H-
7), 10.54 (s, 2H, H-8), 7.99 (dt, 2H, J = 8.6, 2.2, H-4), 7.71 (dt, 2H, J =
8.6, 2.2, H-5), 7.65 (dd, 4H, J = 8.5, 0.9, H-1), 7.32 (ddt, 4H, J = 8.5, 7.4,
1.8, H-2), 7.06 (tt, 2H, J = 7.4, 1.0, H-3), 2.79 (ddd, 2H, J = 14.1, 9.4,
6.3, H-9′), 2.61 (ddd, 2H, J = 14.4, 9.5, 6.1, H-9), 1.40−1.61 (m, 4H, H-
10), 1.11−1.25 (m, 8H, H-11, H-12), 0.74 (t, 6H, J = 7.1, H-13).
129.9, 129.6, 128.9, 128.5, 126.9, 121.1, 112.7, 10.3.
1-[(4-Bromobenzoyl)amino]-N,N′-bis(4-chlorophenyl)-2,5-di-
methyl-N-phenyl-1H-pyrrole-3,4-dicarboxamide (14). Light brown,
crystalline. Anal. Calcd for C27H21BrCl2N4O3: C, 54.0; H, 3.5; N, 9.3.
Found: C, 53.7; H, 3.6; N, 9.3. λmax (BaSO4) (nm): 213, 280, 317. νmax
(cm−1): 3247 (N−H); 3128, 3086, 3060, 3037 (CAr−H); 2975, 2920
(C−H); 1717, 1697, 1665, 1638 [amide I: ν(CO)]; 1609; 1591
(CArCAr); 1562, 1550, 1511 [amide II: ν(C−N), δ(N−H)]; 1506;
1492, 1482 (CArCAr); 1456; 1435 δ(C−H); 1422; 1401; 1326, 1306,
1298, 1291, 1272, 1251, 1243 [amide III: ν(C−N), δ(N−H)]; 1199,
1189; 1178; 1111, 1095, 1070 δ(C−H)in plane; 1046; 1012; 945; 929;
908; 896; 866; 840, 825, 821 ν(N−N); 808; 788; 766, 750, 713, 699
1
[amide IV: δ(OCN)]; 666; 648; 642; 628; 594. H NMR (C2D6OS,
600 MHz): δ 11.81 (s, 1H, H-7), 10.73 (s, 2H, H-8), 7.95 (d, 2H, J =
1655
https://dx.doi.org/10.1021/acs.joc.0c02451
J. Org. Chem. 2021, 86, 1649−1658

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
13C{1H} NMR (C2D6OS, 75 MHz): δ 165.2, 164.1, 139.0, 137.5, 136.2,
130.1, 129.4, 129.0, 128.6, 123.3, 119.5, 113.1, 30.8, 28.2, 24.0, 21.5,
13.6.
ν(CN); 1622; 1611; 1597 (CArCAr); 157, 1561, 1522 [amide II:
ν(C−N), δ(N−H)]; 1491 (CArCAr); 1447 δ(C−H); 1421; 1379;
1346; 1311, 1303, 1289, 1273, 1256 [amide III: ν(C−N), δ(N−H)];
1225; 1178; 1157; 1149; 1141; 1096, 1079, 1071, 1062 δ(C−H)in plane
;
1-[(4-Aminobenzoyl)amino]-N,N′-diphenyl-2,5-dipentyl-1H-pyr-
role-3,4-dicarboxamide Hemihydrate (18). Light brown, crystalline.
Anal. Calcd for C35H42N5O3.5: C, 71.4; H, 7.2; N, 11.9. Found: C, 71.4;
H, 7.1; N, 11.7. λmax (BaSO4) (nm): 205, 285, 434. νmax (cm−1): 3487,
3390 ν(NH2); 3254, 3232 ν(N−H); 3131, 3056, 3040 ν(CAr−H);
2959, 2926, 2870, 2855 ν(C−H); 1652, 1621 [amide I: ν(CO)];
1596 ν(CArCAr); 1561, 1538 [amide II: ν(C−N), δ(N−H)]; 1499
ν(CArCAr); 1466; 1439 δ(C−H); 1381; 1311, 1289, 1254 [amide III:
ν(C−N), δ(N−H)]; 1215; 1206; 1184; 1155; 1132; 1116, 1103 δ(C−
H)in plane; 1073; 1029; 99; 983; 965; 943; 935; 916; 898; 872; 837
1031; 1026; 1002; 996; 973; 963; 935, 924; 906; 844, 830 ν(N−N);
800; 767, 715, 695, 688 [amide IV: δ(OCN)]; 666; 646; 617; 600; 569.
Imine form. 1H NMR (C2D6OS, 300 MHz): δ 11.39 (br s, 1H), 10.37
(br s, 1H), 7.87 (d, 2H, J = 7.0), 7.59 (d, 2H, J = 7.5), 7.53 (t, 1H, J =
5.5), 7.51 (t, 2H, J = 5.6), 7.33 (t, 2H, J = 7.5), 7.09 (t, 1H, J = 7.4), 3.61
(s, 2H), 2.11 (s, 3H). 13C{1H} NMR (C2D6OS, 75 MHz): δ 167.1,
166.7, 138.3, 133.6, 131.4, 128.7, 128.4, 128.3, 127.4, 123.8, 119.5, 46.3,
1
24.0. Enamine form, isomer “Z”. H NMR (C2D6OS, 300 MHz): δ
10.33 (s, 1H), 9.25 (s, 1H), 8.26 (s, 1H), 7.96 (d, 2H, J = 6.8), 7.5 (m,
3H), 7.28 (t, 2H, J = 7.9), 7.19 (t, 2H, J = 7.5), 6.88 (t, 1H, J = 7.3), 5.08
(s, 1H), 2.29 (s, 3H).
1
ν(N−N); 798; 750, 692 [amide IV: δ(OCN)]; 627; 602. H NMR
(C2D6OS, 300 MHz): δ 11.09 (s, 1H, H-7), 10.54 (s, 2H, H-8), 7.70 (d,
2H, J = 8.7, H-4), 7.65 (dd, 4H, J = 8.5, 1.0, H-1), 7.32 (ddt, 4H, J = 8.5,
7.3, 1.7, H-2), 7.06 (tt, 2H, J = 7.4, 1.1, H-3), 6.65 (d, 2H, J = 8.7, H-5),
5.91 (s, 2H, NH2), 2.77 (ddd, 2H, J = 14.1, 9.5, 6.2, H-9′), 2.57 (ddd,
2H, J = 14.2, 9.5, 5.9, H-9), 1.37−1.62 (m, 4H, H-10), 1.10−1.34 (m,
8H, H-11, H-12), 0.75 (t, 6H, J = 7.0, H-13). 13C{1H} NMR (C2D6OS,
75 MHz): δ 165.8, 164.3, 152.9, 139.1, 136.7, 129.3, 128.6, 123.2,
119.4, 117.4, 112.6, 112.6, 30.9, 28.2, 24.1, 21.4, 13.6.
(3E)-3-{2-[(4-Chlorophenyl)carbonyl]hydrazinylidene}-N-phenyl-
butanamide (A1B4). White, crystalline. Anal. Calcd for
C17H16ClN3O2: C, 61.9; H, 4.9; N, 12.7. Found: C, 61.7; H, 4.9; N,
12.7. νmax (cm−1): 3283, 3252 (N−H); 3201, 3145, 3108, 3093, 3046,
3025 (CAr−H); 2996, 2956, 2900, 2883, 2835 (C−H); 1656 [amide I:
ν(CO)]; 1652 ν(CN); 1622; 1611; 1592 (CArCAr); 1564,
1558; 1538, 1527 [amide II: ν(C−N), δ(N−H)]; 1499, 1485 (CAr
CAr); 1446 δ(C−H); 1428; 1381; 1344; 1318; 1309, 1300, 1277, 1272,
1249 [amide III: ν(C−N), δ(N−H)]; 1222; 1178; 1158; 1152; 1138;
1109, 1096, 1080 δ(C−H)in plane; 1060; 1027; 1014; 1000; 989; 967;
961; 950; 937; 906; 848, 840, 828 ν(N−N); 780; 763, 756, 725, 692
1
[amide IV: δ(OCN)]; 677; 626; 602; 569. Imine form. H NMR
(C2D6OS, 300 MHz): δ 11.42 (br s, 1H), 10.36 (br s, 1H), 7.88 (d, 2H,
J = 6.0), 7.61 (d, 2H, J = 8.5), 7.58 (m, 2H), 7.33 (t, 1H, J = 5.6), 7.30
(m, 1H), 7.06 (m, 1H), 3.62 (s, 2H), 2.11 (s, 3H). 13C{1H} NMR
(C2D6OS, 75 MHz): δ 167.0, 166.6, 138.9, 129.6, 129.3, 128.7, 128.6,
1
128.5, 128.3, 123,2, 119.0, 46.3, 24.0. Enamine form, isomer “Z”. H
1-({6-[1-(Hexanoylamino)-2,5-dimethyl-N,N′-diphenyl-1H-pyrro-
lo-3,4-dicarboxamido]-6-oxohexanoyl}amino)-2,5-dimethyl-N,N′-
diphenyl-1H-pyrrole-3,4-dicarboxamide Monohydrate (19). Light
brown, crystalline. Anal. Calcd for C46H48N8O7: C, 67.0; H, 5.9; N,
13.6. Found: C, 66.9; H, 5.8; N, 13.6. λmax (BaSO4) (nm): 216, 259,
283, 306. νmax (cm−1): 3289, 3265 (N−H); 3145, 3096, 3060, 3040
(CAr−H); 2959, 2938, 2898, 2876 (C−H); 1679, 1666 [amide I:
ν(CO)]; 1610; 1595 (CArCAr); 1566, 1521 [amide II: ν(C−N),
δ(N−H)]; 1500 (CArCAr); 1444 δ(C−H); 1412; 1377; 1363; 1331,
1311; 1255 [amide III: ν(C−N), δ(N−H)]; 1204; 1186; 1156; 1133,
1116, 1104 δ(C−H)in plane; 1076; 1048; 1027; 967; 936; 921; 893; 862;
830 ν(N−N); 790; 763, 747, 688 [amide IV: δ(OCN)]; 631; 568. 1H
NMR (C2D6OS, 300 MHz): δ 11.13 (s, 2H, H-7), 10.67 (s, 4H, H-8),
7.66 (dd, 8H, J = 8.5, 0.9, H-1), 7.33 (ddt, 8H, J = 8.5, 7.4, 1.9, H-2),
7.08 (tt, 4H, J = 7.4, 1.0, H-3), 2.47 (t, 4H, J = 6.0, H-15), 2.28 (s, 12H,
H-9), 1.75 (t, 4H, J = 6.0, H-16). 13C{1H} NMR (C2D6OS, 75 MHz): δ
171.5, 164.2, 139.0, 132.5, 128.7, 123.3, 119.5, 112.6, 32.7, 24.5, 10.3.
3-Oxo-N-phenyloctanamide (A3). White, crystalline. Anal. Calcd
for C14H19NO2: C, 72.1; H, 8.2; N, 6.0. Found: C, 71.7; H, 8.2; N, 6.0.
νmax (cm−1): 3287, 3254 (N−H); 3196, 3137, 3080, 3066, 3046, 3022
(CAr−H); 2951, 2931, 2898, 2869 (C−H); 1721, 1713, 1658 [amide I:
ν(CO)]; 1620; 1605; 1599 (CArCAr); 1557, 1550 [amide II: ν(C−
N), δ(N−H)]; 1500, 1485 (CArCAr); 1467; 1445 δ(C−H); 1413;
1374; 1347; 1328; 1321; 1311; 1301; 1266, 1240, 1233 [amide III:
ν(C−N), δ(N−H)]; 1202; 1176; 1170; 1160; 1155; 1124; 1074; 1063;
1040; 1029; 1007; 1001; 986; 962; 903; 884; 841; 754, 740, 716, 692
[amide IV: δ(OCN)]; 666; 591. 1H NMR (C2D6OS, 300 MHz): δ 9.16
(s, 1H, H-4), 7.54 (dd, 2H, J = 8.4, 0.9, H-1), 7.32 (ddt, 2H, J = 8.4, 7.5,
1.8, H-2), 7.11 (tt, 1H, J = 7.5, 0.9, H-3), 3.55 (s, 2H, H-5), 2.57 (t, 2H, J
= 7.4, H-6), 1.62 (quintet, 2H, J = 7.4, H-7), 1.26−1.36 (m, 4H, H-8, H-
9), 0.90 (t, 3H, J = 7.1, H-10). 13C{1H} NMR (C2D6OS, 75 MHz): δ
207.8, 163.5, 137.5, 128.9, 124.5, 120.1, 49.0, 44.1, 31.1, 23.0, 22.3,
13.8.
NMR (C2D6OS, 300 MHz): δ 10.66 (s, 1H), 10.22 (br s, 1H), 8.28 (s,
1H), 7.97 (d, 2H, J = 8.6), 7.5 (m, 4H), 7.19 (t, 2H, J = 7.5), 6.89 (t, 1H,
J = 7.3), 5.08 (s, 1H), 2.29 (s, 3H).
(2E,3Z)-2,3-Bis[2-(phenylcarbonyl)hydrazinylidene]-N-phenylbu-
tanamide (C1). White, crystalline. νmax (cm−1): 3236 (N−H); 3149,
3108, 3041, 3025 (CAr−H); 3003, 2978, 2907 (C−H); 1669 [amide I:
ν(CO)]; 1650 ν(CN); 1619; 1596 (CArCAr); 1582, 1547, 1528
[amide II: ν(C−N), δ(N−H)]; 1501, 1488 (CArCAr); 1456; 1423;
1334; 1332; 1322; 1309, 1302, 1247, 1224 [amide III: ν(C−N), δ(N−
H)]; 1193; 1163; 1139, 1110 δ(C−H)in plane; 1073; 1045; 1025; 1000;
970; 935; 909; 896; 854, 842, 822, 809 ν(N−N); 798; 779; 754, 701,
690 [amide IV: δ(OCN)]; 666; 626.
(2E,3Z)-2,3-Bis{2-[(4-chlorophenyl)carbonyl]hydrazinylidene}-N-
phenylbutanamide (C4). White, crystalline. Anal. Calcd for
C24H19Cl2N5O3: C, 58.1; H, 3.9; N, 14.1. Found: C, 58.6; H, 4.0; N,
13.9. νmax (cm−1): 3225 (N−H), 3169, 3115, 3041, 3024 (CAr−H),
3003, 2978 (C−H), 1682 [amide I: ν(CO)]; 1667, 1645 ν(CN);
1617; 1595 (CArCAr); 1572, 1550, 1538, 1525 [amide II: ν(C−N),
δ(N−H)]; 1502; 1493; 1484; 1471; 1464; 1455; 1420; 1394; 1372;
1329; 1314, 1302, 1250, 1222 [amide III: ν(C−N), δ(N−H)]; 1185;
1170; 1146; 1116; 1108; 1098; 1093; 1080; 1044, 1012 δ(C−H)in plane
;
967; 933; 910; 899; 845, 830 ν(N−N); 785; 758; 736; 691 [amide IV:
δ(OCN)]; 677, 638; 624; 563.
Single-Crystal X-ray Data for Compounds A1B4, C4, and 4.
Crystal structure data for A1B4: C17H16ClN3O2, M = 329.78,
monoclinic, a = 12.821(5) Å, b = 10.891(5) Å, c = 12.841(5) Å, V =
1621.8(12) Å3, T = 113(2) K, space group P21/c, Z = 4, 19921
reflections measured, 3349 unique (Rint = 0.0368). The final wR(F2)
was 0.0820 (all data). Crystallographic data (including structure
factors) for A1B4 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number
CCDC 950456.
Crystal structure data for C4: C24H19Cl2N5O3, M = 496.34, triclinic,
(3E)-N-Phenyl-3-[2-(phenylcarbonyl)hydrazinylidene]-
butanamide (A1B1). White, crystalline. Anal. Calcd for C17H17N3O2:
C, 69.1; H, 5.8; N, 14.2. Found: C, 69.3; H, 5.8; N, 14.2. νmax (cm−1):
3282, 3249 (N−H); 3198, 3140, 3091, 3049, 3029 (CAr−H); 2997,
2952, 2935, 2913, 2880, 2831 (C−H); 1659 [amide I: ν(CO)]; 1649
a = 9.113(5) Å, b = 11.090(5) Å, c = 11.922(5) Å, V = 1106.2(9) Å3, T =
̅
110(2) K, space group P1, Z = 2, 14276 reflections measured, 4576
unique (Rint = 0.0378). The final wR(F2) was 0.0981 (all data).
Crystallographic data (including structure factors) for C4 have been
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Article
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 950454.
80, 229−233. (c) Hamilton, S.; Hepher, M. J.; Sommerville, J.
Polypyrrole materials for detection and discrimination of volatile
organic compounds. Sens. Actuators, B 2005, 107, 424−432.
(4) Mathew, P.; Asokan, C. V. An efficient synthesis of highly
substituted pyrroles from β-oxodithiocarboxylates. Tetrahedron 2006,
62, 1708−1716.
(5) (a) Jones, R. A. Pyrroles, The Synthesis, Reactivity, and Physical
Properties of Substituted Pyrroles. Part II; Wiley: New York, 1992.
(b) Black, D. St. C.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Comprehensive Heterocyclic Chemistry II; Elsevier: Oxford, U.K., 1996;
Vol. 2, p 39.
Crystal structure data for 4: C27H23ClN4O3, M = 486.94, triclinic, a =
7.257(5) Å, b = 12.602(5) Å, c = 13.243(5) Å, V = 1146.5(10) Å3, T =
̅
110(2) K, space group P1, Z = 2, 15045 reflections measured, 4744
unique (Rint = 0.0203). The final wR(F2) was 0.0893 (all data).
Crystallographic data (including structure factors) for 4 have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 950455.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02451.
■
sı
(6) Knorr, L. Synthese von pyrrolderivaten. Ber. Dtsch. Chem. Ges.
1884, 17, 1635−1642.
(7) Paal, C. Synthese von Thiophen-und Pyrrolderivaten. Ber. Dtsch.
Chem. Ges. 1885, 18, 367−371.
1H NMR, 13C NMR, and IR spectra of final compounds
1−19 and selected substrates and intermediates; lists of
NMR signal shifts for 1−19; and structures of A1B4, C4,
and 4 (PDF)
(8) Hantzsch, A. Pyrrole synthesis. Ber. Dtsch. Chem. Ges. 1890, 23,
1474−1476.
(9) (a) Martín, R.; Larsen, C. H.; Cuenca, A.; Buchwald, S. L. Cu-
Catalyzed Tandem C− N Bond Formation for the Synthesis of Pyrroles
and Heteroarylpyrroles. Org. Lett. 2007, 9, 3379−3382. (b) Wang, Y.;
Bi, X.; Li, D.; Liao, P.; Wang, Y.; Yang, J.; Zhang, Q.; Liu, Q. Iron-
catalyzed synthesis of polysubstituted pyrroles via [4C+ 1N] cyclization
of 4-acetylenic ketones with primary amines. Chem. Commun. 2011, 47,
Accession Codes
CCDC 950454−950456 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
809−811. (c) Ciez, D. A direct preparation of N-unsubstituted pyrrole-
̇
2, 5-dicarboxylates from 2-azidocarboxylic esters. Org. Lett. 2009, 11,
4282−4285. and references cited therein
(10) (a) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.;
Santeusanio, S. Synthesis of functionalized pyrroles via catalyst- and
solvent-free sequential three-component enamine-azoene annulation. J.
Org. Chem. 2011, 76, 2860−2866. (b) Li, K.; You, J. Cascade Oxidative
Coupling/Cyclization: A Gateway to 3-Amino Polysubstituted Five-
Membered Heterocycles. J. Org. Chem. 2016, 81, 2327−2339. (c) Sha,
Q.; Arman, H.; Doyle, M. Three-Component Cascade Reactions with
2,3-Diketoesters: A Novel Metal-Free Synthesis of 5-Vinyl-pyrrole and
4-Hydroxy-indole Derivatives. Org. Lett. 2015, 17, 3876−3879.
AUTHOR INFORMATION
Corresponding Author
Janusz Szklarzewicz − Faculty of Chemistry, Jagiellonian
University, 30-387 Kraków, Poland; orcid.org/0000-
0001-9747-9238; Email: szklarze@chemia.uj.edu.pl
■
Authors
́
́
(11) (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Recent advances
in the synthesis of pyrroles by multicomponent reactions. Chem. Soc.
Rev. 2014, 43, 4633−4657. (b) Minetto, G.; Raveglia, L. F.; Sega, A.;
Taddei, M. Microwave-Assisted Paal-Knorr Reaction - Three-Step
Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and
Thiophenes. Eur. J. Org. Chem. 2005, 2005, 5277−5288. (c) Chen, X.;
Xie, Y.; Xiao, X.; Li, G.; Deng, Y.; Jiang, H.; Zeng, W. Rh(III)-catalyzed
chelation-assisted intermolecular carbenoid functionalization of α-
imino Csp3−H bonds. Chem. Commun. 2015, 51, 15328−15331.
(12) (a) Bolm, C. Vanadium-catalyzed asymmetric oxidations. Coord.
Chem. Rev. 2003, 237, 245−256. (b) Licini, G.; Conte, V.; Coletti, A.;
Mba, M.; Zonta, C. Recent advances in vanadium catalyzed oxygen
transfer reactions. Coord. Chem. Rev. 2011, 255, 2345−2357.
(13) Ligtenbarg, A. G. J.; Spek, A. L.; Hage, R.; Feringa, B. L.
Vanadium (V) complexes based on a bis (pyridine)-imine ligand (HL);
synthesis and crystal structure of a dioxovanadium (V) complex
involving a ligand cyclisation. J. Chem. Soc., Dalton Trans. 1999, 659−
661.
Patrycja Paciorek − Faculty of Chemistry, Jagiellonian
University, 30-387 Kraków, Poland
Bartosz Trzewik − Faculty of Chemistry, Jagiellonian
University, 30-387 Kraków, Poland
Dariusz Ciez − Faculty of Chemistry, Jagiellonian University,
̇
30-387 Kraków, Poland
Wojciech Nitek − Faculty of Chemistry, Jagiellonian University,
30-387 Kraków, Poland
Maciej Hodorowicz − Faculty of Chemistry, Jagiellonian
University, 30-387 Kraków, Poland; orcid.org/0000-
0003-4210-3625
Anna Jurowska − Faculty of Chemistry, Jagiellonian University,
30-387 Kraków, Poland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02451
Notes
(14) (a) Yamamoto, K.; Oyaizu, K.; Tsuchida, E. Catalytic Cycle of a
Divanadium Complex with Salen Ligands in O2 Reduction: Two-
Electron Redox Process of the Dinuclear Center (salen= N, N
‘-Ethylenebis (salicylideneamine)). J. Am. Chem. Soc. 1996, 118,
12665−12672. (b) Oyaizu, K.; Yamamoto, K.; Yoneda, K.; Tsuchida, E.
Multielectron Redox Process of Vanadium Complexes in Oxidation of
Low-Coordinate Vanadium (III) to Oxovanadium (V) with Dioxygen.
Inorg. Chem. 1996, 35, 6634−6635.
(15) (a) Bunce, S.; Cross, R. J.; Farrugia, L. J.; Kunchandy, S.; Meason,
L. L.; Muir, K. W.; O'Donnell, M.; Peacock, R. D.; Stirling, D.; Teat, S. J.
Chiral Schiff base complexes of copper (II), vanadium (IV) and nickel
(II) as oxidation catalysts. X-ray crystal structures of [Cu (R-salpn)
(OH2)] and [Cu ( -busalcx)]. Polyhedron 1998, 17, 4179−4187.
(b) Gupta, K. C.; Sutar, A. K. Catalytic activities of Schiff base transition
metal complexes. Coord. Chem. Rev. 2008, 252, 1420−1450.
The authors declare no competing financial interest.
REFERENCES
■
(1) Black, D. St. C. In Science of Synthesis; Maas, G., Ed.; Georg
Thieme Verlag: Stuttgart, Germany, 2001; pp 441−552.
(2) Sundberg, R. J.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. In
Comprehensive Heterocyclic Chemistry II; Pergamon Press: Oxford, U.K.,
1996; Vol. 2, p 119.
(3) (a) Lazerges, K. I.; Chane-Ching, S.; Aeiyach, S.; Chelli, B.;
Peppin-Donnat, M.; Billon, L.; Lombard, F.; Maurel, M.; Jouini, J.
Paramagnetic pyrrole-based semiconductor molecular material. J. Solid
̈
State Electrochem. 2009, 13, 231−238. (b) Kros, A.; van Hovel, S. W. F.
M.; Nolte, R. J. M.; Sommerdijk, N. A. J. M. A printable glucose sensor
based on a poly (pyrrole)-latex hybrid material. Sens. Actuators, B 2001,
1657
https://dx.doi.org/10.1021/acs.joc.0c02451
J. Org. Chem. 2021, 86, 1649−1658

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(16) (a) Thiyagarajan, B.; Kerr, M. E.; Bruno, J. W. Autoxidation of an
Electron-Rich Organometallic. Mechanism of the Reaction of a
Substituted Niobocene Compound with Dioxygen. Inorg. Chem.
1995, 34, 3444−3452. (b) Simandi, L. I. Dioxygen Activation and
Homogeneous Catalytic Oxidation; Elsevier: Amsterdam, 1991; p 66.
(c) Sheldon, R. A.; Kochi, J. M. Metal-Catalyzed Oxidation of Organic
Compounds; Academic Press: New York, 1981.
(17) Crystallographic data (excluding structure factors) for A1B4, C4,
and 4 have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication numbers CCDC 950454, 950456,
and 950455, respectively.
(18) Cadman, M. L. F.; Crombie, L.; Freeman, S.; Mistry, J. The
chemoselective cyclisation of unsymmetrical γ-diketones to cyclo-
pentenones by directed aldol reaction using a magnesium chelate. J.
Chem. Soc., Perkin Trans. 1 1995, 11, 1397−1408.
(19) Jendralla, H.; Baader, E.; Bartmann, W.; Beck, G.; Bergmann, A.;
Granzer, E.; Von Kerekjarto, B.; Kesseler, K.; Krause, R.; Schubert, W.;
Wess, G. Synthesis and biological activity of new HMG-CoA reductase
inhibitors. 2. Derivatives of 7-(1H-pyrrol-3-yl)-substituted-3,5-dihy-
droxyhept-6 (E)-enoic (-heptanoic) acids. J. Med. Chem. 1990, 33, 61−
70.
(20) Xiang, D.; Wang, K.; Liang, Y.; Zhou, G.; Dong, D. A Facile and
Efficient Synthesis of Polyfunctionalized Pyridin-2 (1 H)-ones from β-
Oxo Amides under Vilsmeier Conditions. Org. Lett. 2008, 10, 345−348.
(21) CrysAlis PRO; Oxford Diffraction Ltd.: Yarnton, England, 2010.
(22) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.;
Spagna, R. SIR97: a new tool for crystal structure determination and
refinement. J. Appl. Crystallogr. 1999, 32, 115−119.
(23) Sheldrick, G. M. SHELXL. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112−122.
̇
(24) Bankowska, Z.; Zadrozna, I. Enolization of methyl derivatives of
ethyl acetonitrile. I. Preparation and infrared, ultraviolet, and nuclear
magnetic resonance spectra. Rocz. Chem. 1968, 42, 1241−1251.
(25) Kagan, H. B.; Heng Suen, Y. Reaction de reformatsky sur les
nitriles. I. Preparation de beta-ceto-esters non substitues mono ou
disubstitues en alpha. Bull. Soc. Chim. Fr. 1966, 1819−1822.
(26) P.403740 (WIPO ST 10/C PLP.403740).
1658
https://dx.doi.org/10.1021/acs.joc.0c02451
J. Org. Chem. 2021, 86, 1649−1658